PROJECT SUMMARY The overall objective of the Mayo Clinic Center for Cell Signaling in Gastroenterology (C-SiG) is to exploit signaling pathways in gastrointestinal cells to improve the health of patients with digestive diseases. To do this, C-SiG provides a robust infrastructure, thematic platforms, and career development opportunities to integrate and amplify impactful investigation along the discovery-translation-application paradigm. Our Research Base now consists of 68 scientists (15% growth) involving 18 departments and $23.7 million (direct costs, 2.5% growth) in digestive disease-related funding. Responding to members' evolving interests and scientific advances, we've re-aligned members into three interconnected Mechanistic Research Themes (intracellular signaling, cell-to-cell communication, and genetics/epigenetics), each intersecting with three Disease Focus Groups (liver pathobiology, enteric neurosciences, inflammation/transformation), a matrix that fosters both discovery and disease relevant investigation. Our ongoing CENTRAL HYPOTHESIS is that advances in care of patients with digestive diseases requires a facilitative infrastructure supporting meaningful interactions among multidisciplinary scientists investigating cellular mechanisms, pathways, and therapeutic targets to enhance rapid translation of basic discoveries into clinical trials. Our OVERALL SPECIFIC AIMS are to: i) Foster multidisciplinary research by expanding technical and collaborative capabilities of established GI scientists and attracting investigators from other disciplines; ii) Identify and nurture new GI investigators via a peer-reviewed Pilot and Feasibility (P/F) Program including career development workshops, curricula, and structured mentorship (19/26, 73% of P/F recipients achieving federal funding); iii) Offer core-based specialized equipment, technologies, methodologies, reagents, and expertise (Optical Microscopy, Clinical, and Gene Editing and Epigenomics Cores), with continuous core menu updates, quality assurance and assessments, and project management oversight in response to member feedback; iv) Support a robust Enrichment Program; and v) Promote interactions between C-SiG with other NIDDK centers at Mayo (e.g., PKD Center) and existing DDRCCs, especially in the Midwest (i.e., Midwest DDRCC Alliance). Our global efforts have resulted in 215 manuscripts, with 56% percent intra- and 44% inter-thematic publications (70% involving two or more members). Importantly, we've made critical advances in understanding disease pathogenesis relevant to signal transduction, cell-to-cell communication and genetics/epigenetics, thereby identifying potential disease modifying targets.